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The following article by Robert Cook-Deegan
appeared in Genomics, Volume 5, pp 661-663 (October, 1989)
by Academic Press, Inc.(1) . It describes
the genesis of the U.S. Human Genome Project.

The
Alta Summit, December 1984

Alta is a ski area nestled among the Wasatch Mountains (note: original text
said Saguache Mountains) in Utah, a winding 40-minute drive southeast
from Salt Lake City. From December 9 to 13, 1984, visitors were isolated
by repeated blizzards. The slopes were covered most mornings with Utah's
renowned fine light powder, which beckoned skiers to cut its virgin surface.

For those 5 days, Alta was also a capital of human
genetics. Many historical threads in the fabric that
later became the Human Genome Project wind through that
meeting, although it was not a meeting on mapping or
sequencing the human genome. Through happenstance and
historical accident, Alta links human genome projects to
research on the effects of the atomic bombs dropped on
Hiroshima and Nagasaki 40 years earlier. If genome
projects prove important to biology, then historians will
note the Alta meeting.

The Alta meeting was sponsored by the Department of
Energy (DOE) and the International Commission for
Protection Against Environmental Mutagens and
Carcinogens. It was initiated by David Smith of DOE and
Mortimer Mendelsohn of the Lawrence Livermore National
Laboratory, who turned over final organization to Raymond
White of the Howard Hughes Medical Institute at the
University of Utah.

The purpose was to ask those working on the front
lines of DNA analytical methods to address a specific
technical question: could new methods permit direct
detection of mutations, and more specifically could any
increase in the mutation rate among survivors of the
Hiroshima and Nagasaki bombings be detected (in them or
in their children)? The idea behind the Alta meeting came
from another meeting on March 4 and 5, 1984, in
Hiroshima, at which new DNA analytical tools were deemed
second highest priority for human mutations research,
just behind establishing cell lines from atomic bomb
survivors, their progeny, and controls. Those attending
the Alta meeting in December (see Table 1) were drawn
from a variety of backgrounds, and many had never met
each other. Most said in interviews later that they came
to the meeting quite skeptical, but left thinking it had
been one of the best scientific meetings they ever
attended (Interviews, 1987, 1988).

The principal conclusion of the meeting was,
ironically, that methods were incapable of measuring
mutations with sufficient sensitivity, unless an
enormously large, complex, and expensive program were
undertaken. Technical obstacles thus thwarted attainment
of the main goal of the meeting, yet the meeting left a
profusion of new ideas in its wake, some of which later
washed ashore to be incorporated into various genome
projects. Five years later, there is still no sensitive
assay for human heritable mutations, but there are genome
programs at NIH, at DOE, and in several foreign nations.

Excitement about the new methods blossomed at Alta
despite, or perhaps because of, the wintry isolation. As
Mortimer Mendelsohn noted in his internal report to DOE:

It was clear from the outset that the ingredients
for a successful meeting [were present] and the
result far exceeded expectation. Once the point of
the exercise was clear to everyone, a remarkable
atmosphere of cooperation and mutual creativity
pervaded the meeting. Excitement was infectious and
ideas flowed rapidly from every direction, with many
ideas surviving to the end. (Mendelsohn, 1985).

John Mulvihill began the meeting by reviewing
epidemiological studies of human mutations. Studies that
could theoretically have detected a threefold increase in
mutations had not found any. James Neel spoke about
measurement of mutations among Hiroshima-Nagasaki
survivors, estimating that the likely mutation rate was
10-8 per base pair per generation (or roughly 30 new
mutations per genome per generation), indistinguishable
from that of Japanese controls and in the same general
range as that estimated by epidemiological methods and
detection of protein variants among other
"normal" populations. Several of the technical
consultants commented on the passionate devotion Neel
brought to the study of Hiroshima and Nagasaki victims,
and how his demeanor set the tone for lively and
cooperative exchanges throughout the meeting.

Existing methods had failed to detect an anticipated
increase in mutations among the more than 12,000 children
of Hirsohima-Nagasaki survivors (whose parents received
an average 43 rad). Calculations showed that to measure a
30% increase in the mutation rate, roughly what would be
expected from the average dose, one would have to examine
4.5 x 10(10) bp in the children, and 4 to 5
times more in the parents (Delahanty, 1986). In fact, the
DNA methods were at least an order of magnitude short of
being able to detect the expected impact from atomic bomb
exposure among survivors; they could only detect
differences expected from radiation exposure well above
the lethal dose (and hence not measurable). The question
was whether there were new technical means that would get
around the problems. The answer was no, but the process
of thinking about it forced many novel ideas to the
surface.

George Church began to ruminate on the ideas that
culminated in multiplex sequencing. He said later that
discussions with Maynard Olson, Richard Myers, and others
helped him crystallize his inchoate ideas. (David Smith
recalled watching George Church disappear in a cloud of
new-fallen powder one afternoon, and worrying about the
future of DNA sequencing technology.)

Richard Myers showed work using RNase I to cut (and
thus make detectable) single base pair mismatches; he and
Leonard Lerman showed early data using gradients of
denaturing agents embedded in electrophoresis gels as a
way to detect heteroduplexes and mismatches. Myers
credits his roommate for the conference, Maynard Olson,
with clarifying his ideas and permitting him to expand
the RNase I method to mismatches other than C-A
mutations. In a trip report to the Office of Technology
Assessment, Michael Gough characterized the Church and
Myers presentations as technological wonders and called
the two young scientists, then largely unknown, the
"two biggest surprises" of the meeting (Gough,
1984).

Charles Cantor showed how his and David Schwartz's
first pulsed-field gel electrophoresis method could
separate megabase-sized DNA fragments, resolving
individual yeast chromosomes and thus introducing an
enormously powerful method to assess DNA structure on
this scale. He also showed his and Cassandra Smith's
first macrorestriction digest of the Escherichia coli genome,
which suggested the tantalizing possibility of physically
mapping entire genomes by combining restriction cleavage
and pulsed-field gel electrophoresis.

Maynard Olson showed early results of attempting to
construct a physical map of Saccharomyces cerevisiae
using overlapping clones, and also showed good separation
of megabase-sized DNA using a modification of the
Schwartz-Cantor electrophoresis technique. Mendelsohn's
DOE report noted that "while Olson's method would
not presently be chosen for analyzing human mutation
rates, his philosophy of paying careful attention to and
investing in the quantitative, methodological details of
DNA technology had a recurrent and important impact on
the meeting" (Mendelsohn, 1985). Olson later brought
the same core ideas to the National Research Council
Committee on Mapping and Sequencing the Human Genome,
where those ideas, combined with an expansion of goals to
include genetic mapping, helped to forge a consensus that
dedicated genome projects were scientifically worthwhile
(National Research Council, 1988).

At Alta, Elbert Branscomb described the state of the
art in using flow cytometry and immunofluorescence to
detect altered protein products on the surface of red
cells. Branscomb later became the computer modeler and
one of the architects for the Livermore cosmid map of
chromosome 19, now under construction. Tom Caskey
reviewed progress on understanding mutations in the HPRT
locus, and Sherman Weissman reviewed data on the HLA
locus. David Botstein, as always exuding volcanic
enthusiasm peppered with sharp humor, speculated about
pushing the restriction fragment length polymorphism
(RFLP) techniques to their limits--perhaps enough to
detect mutations in the range of 10-7 per base pair per
generation. Unfortunately, this was still shy of what
would be needed to detect mutations among the
Hiroshima-Nagasaki survivors, unless an unrealistically
massive effort were mounted. Ray White talked about
applying RFLP methods to the Y chromosomes originating
from a single Mormon progenitor of 1850 (who by now has
thousands of male descendants) to examine changes in the
part of the Y chromosome outside the pseudoautosomal
region--a part of the genome where changes should
accumulate.

Edwin Southern wound up the scientific session by
addressing the gap between cytogenetic detection and
molecular methods, and his presence was noted by more
than one participant as a moderating influence on the
intellectual pyrotechnics. Southern's discussion of
measuring uv-induced mutations might be seen to presage
the radiation hybrid mapping methods brought to fruition
in 1988 by David Cox and Richard Myers, although the two
approaches are quite independent in origin.

Michael Gough returned from Alta to Washington to work
on the OTA report on detecting heritable mutations. The
report had been requested by Congress in anticipation
that controversies over Agent Orange, radiation exposure
during atmospheric testing in the 1950s, and exposure to
mutagenic chemicals might find their way to court, where
a neutral assessment of the technical feasibility of
detecting mutations would be essential. Gough directed
preparation of Technologies for Detecting Heritable
Mutations in Human Beings until he left OTA in 1985 (U.S.
Congress, 1986). Several Alta participants served either
as contractors or as advisory panel members for that
study. Charles DeLisi, then newly appointed director of
the Office of Health and Environmental Research at DOE,
read a draft of this report in October 1985, and while
reading it first had the idea for a dedicated human
genome project (DeLisi, 1988). The Alta meeting is thus
the bridge from DOE's traditional interest in detection
of mutations to DeLisi's push for a Human Genome
Initiative, and provides one of several historical links
between genome projects and another massive technical
undertaking of the 20th century--the Manhattan project.

4. Interviews with David Botstein, 22 August 1988;
Charles Cantor, 19 August 1988; George Church, 14
November 1988; Charles DeLisi, 6 January 1987 and 7
October 1988; Maynard Olson, 28-30 April 1988; David
Schwartz, 6 January 1987; and David Smith, 22 December
1988.

*Article from Genomics,
Volume 5, pp 661-663 (October, 1989) by Academic Press,
Inc., reproduced by permission of the publisher. This
material may not be reproduced, stored in a retrieval
system, or transmitted in any form or by any means
without the prior written permission of the publisher.

Human Genome Project 1990–2003

The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.

Published from 1989 until 2002, this newsletter facilitated HGP communication, helped prevent duplication of research effort, and informed persons interested in genome research.

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Unless otherwise noted, publications and webpages on this site were created for the U.S. Department of Energy Human Genome Project program and are in the public domain. Permission to use these documents is not needed, but credit the U.S. Department of Energy Human Genome Project and provide the URL http://www.ornl.gov/hgmis when using them. Materials provided by third parties are identified as such and not available for free use.